RESISTANCE PATTERN OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE TO QUINOXALINE S-2720

The human immunodeficiency virus type 1 (HIV-1)-specific reverse trans criptase (RT) inhibitor quinoxaline S-2720 showed a more-potent inhibi tory effect on HIV-1-induced cytopathicity in CEM cells than either ne virapine, pyridinone L-697,661, bis-heteroarylpiperazine (BHAP) U-8820 4, TSAO ',2''-oxathiole-2'',2''-dioxide)-N-3-ethylthymine, or ydro-5-m ethylimidazo[4,5,1-jk][1,4-benzodiazepin-2 (IH)-one (TIBO) R82913. The quinoxaline derivative was also markedly more inhibitory to the mutan t HIV-1 strains containing in their RT Ile 100, Asn-103, Ala-106, Lys- 138, Cys-181, or His-188 substitutions than were the other HIV-1-speci fic RT inhibitors. Moreover, quinoxaline S-2720 totally prevented HIV- 1 infection and emergence of drug-resistant mutant virus strains in CE M cell cultures at concentrations (i.e., 0.35 mu M) that are 10- to 25 -fold lower than those required for BHAP U-88204 and nevirapine to kno ck out the virus. Also, the concentration-response curve for S-2720 wa s markedly steeper than for BHAP and nevirapine, as reflected by the r atio of the 95% to the 50% antivirally effective concentration. Lower concentrations of quinoxaline dominantly lead to the appearance of the Ala-106 RT mutation, causing low-level resistance to the compound. At higher quinoxaline concentrations, the Glu-190 RT and/or the Cys-181 RT mutation is added to the Ala-106 mutation, whereas at the highest q uinoxaline concentrations, the Ala-106 mutation tends to disappear fro m the virus pool, leaving the Glu-190 RT and Cys-181 RT mutations as t he only mutations conferring high-level resistance to the compound.